Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide among all human cancer and causes 1 million deaths annually. Despite many promising treatment options, which include surgical resection, alcohol or radiofrequency ablation, chemoembolization, and liver transplantation, long-term prognosis remains poor in patients with advanced disease.
At present, embolization is the most widely used primary treatment for non-resectable HCC and has been the most-used therapy for patients awaiting liver donation for the prevention of HCC progression that might preclude transplantation. Embolization agents are usually administered together with selective intra-arterial cytotoxic agents, among them doxorubicin is most frequently used. Although this regimen significantly delays tumour progression and vascular invasion, this approach only achieves a partial response in patients.
Despite the recent development of new treatment modalities, the need to discover therapeutic molecules to overcome resistance to chemotherapeutic agents of HCC is still urgent. Notch receptors are implicated in proliferation, differentiation and apoptosis. Because of increasing evidence that the Notch signalling pathway is abnormally deregulated in human cancer, Notch receptors are potential targets for selective killing malignant cells.
The four known Notch receptors (Notch1-4) are single-pass transmembrane receptors that mediate signaling from the cell surface to the nucleus regulating proliferation, differentiation and apoptosis at all stages of development. Notch receptors are mainly activated by trans-membrane ligands of the Delta and Serrate/jagged families, which are expressed on the surface of neighboring cells. Ligand-mediated activation of Notch induces the proteolytic cleavage and nuclear translocation of a Notch intracellular domain (NICD) that binds to the transcription factor CBF1/RBP-Jk to trans-activate target genes, including HES1.
Deregulated Notch receptor expression has been reported in a variety of different human tumors. Increased Notch1 protein expression has been observed in human cancers of the breast, pancreas and also in Hodgkin lymphoma. Over-expression of Notch3 and Notch4 proteins has been detected in malignant melanoma, pancreatic cancer and breast cancer.
The Notch1 signaling pathway is activated during rat liver regeneration and over-expression of Notch1 has been found to inhibit the growth of HCC cells in vitro and in vivo.
It appears that constitutive activation of Notch1 may function as a tumor suppressor in small cell lung cancer cells, in prostate cancer cells and in mouse skin by inducing cell growth arrest.
Notch3 has been recently found to be highly expressed in the Human HepG2 liver carcinoma cell line; but up to now there are no studies concerning Notch3 functions in HCC.
In the field of tumors, gene therapy represents a new and promising strategy that relies on the transfer of genetic material into cells to produce a beneficial effect against the disease. Small interfering RNA (siRNA) is an emerging technology that capitalizes on a natural property of all cells to direct the silencing of specific genes by promoting either the degradation or ablating the translation of target mRNAs. Over the past several years a variety of vehicles have been developed to express and deliver short hairpin RNAs (shRNAs), which are efficiently converted into siRNAs by the natural RNA processing machinery of mammalian cells. Thus because of the established high specificity for their target mRNAs, specific shRNAs are being examined for the development of potential new therapies against a variety of human diseases including cancer.
Although it is known that Notch receptors, depending on their levels of expressions in various cellular contexts play a key role in the apoptotic resistance of malignant cells, their mechanism of action remains largely unknown, thus limiting the possibility of medical treatments against tumors related to said receptors.
Concerning the HCC, the medical limits against said disease listed above, underline the need, in the medical field, of drugs providing an effective treatment against the spreading and the survival of the HCC malignant cells.